PROJECT SUMMARY/ABSTRACT Influenza virus epidemics cause significant morbidity and mortality each year. Host determinants of infection severity and pathogenesis remain poorly defined. Sex differences in influenza infection outcomes are well documented, but not well understood mechanistically. Our previous funding from NIAID and VCIID COBRE has enabled us to conduct a genome wide screen of host genetic determinants of influenza virus pathogenesis, using a unique genetic model of natural genetic variation in mice. Our screen has identified two loci, one on chromosome 5 and the other on chromosome X, that significantly modify sex differences in influenza pathogenesis. We propose to begin a dissection of the mechanisms underlying these genetically regulated sex differences. Additionally, we will extend these studies to include young pre-pubertal mice.